Biopolymer compositions for the treatment and prevention of gastric ulcers

ABSTRACT

The invention provides compositions comprising chitosan, manuka honey and one or more additional components that promotes digestive health (e.g., inulin, probiotics) for the treatment and prevention of gastric ulcers (esophageal, stomach, or duodenum) in a mammal (e.g., equine).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Utility application Ser. No.16/489,647, filed Aug. 28, 2019, which is a U.S. national phaseapplication, pursuant to 35 U.S.C. § 371, of PCT InternationalApplication Ser. No.: PCT/US2018/020683, filed Mar. 2, 2018, designatingthe United States and published in English, which claims the benefit ofand priority to U.S. Provisional Application Ser. No. 62/467,000, filedMar. 3, 2017, all of which are incorporated herein by reference in itsentirety.

BACKGROUND OF THE INVENTION

In humans, gastric ulcers, often referred to as peptic ulcers, arepainful sores along the lining of the stomach or the duodenum, the firstsection of the small intestine. Ulcers may be caused by an imbalance inthe digestive fluids present in the stomach. Several factors canincrease the prevalence of gastric ulcers including the use of NSAIDs,alcohol, or tobacco, radiation, serious illness, illness causing excessacid production or infection from Helicobacter pylori. Symptoms ofgastric distress related to gastric ulcers include pain, heartburn, andnausea. Without treatment, gastric ulcers in humans may lead to weightloss, internal bleeding, perforation of the lining of the stomach, orswelling that could create gastric obstruction.

Gastric ulcers are common in other mammals as well, including horses.Horses with ulcers may develop a debilitating condition requiringintervention. EGUS, Equine Gastric Ulcer Syndrome, is a designation usedto describe many aspects of this complicated condition. It is estimatedthat 25-50% of foals, and 60-90% of all horses will experience gastriculcers, and this number climbs when looking at horses in training, suchas thoroughbreds, hunters, jumpers, and eventers.

The equine stomach is segregated into two sections, the non-glandularregion and the glandular region. The non-glandular section makes upapproximately one-third of the equine stomach, with the glandular regionaccounting for the remaining two-thirds of the stomach. Thenon-glandular region lacks glands and is lined with stratified squamousepithelium, whereas the glandular region contains glands that secretehydrochloric acid, pepsin, bicarbonate, and mucus. Many equine gastriculcers are present in the non-glandular region. Horses that receiveNSAIDs or that have certain medical conditions may present with ulcersin the glandular region. Additionally, foals and adult horses may haveulcers in the duodenum.

The glandular region of the equine stomach constantly secreteshydrochloric acid in variable volumes, with or without the presence offeed in the stomach. Adult horses secrete, on average 1.5 liters ofgastric fluids per hour, representing approximately 60 mmoles ofhydrochloric acid per hour. The pH of the equine stomach is variabledepending on section, but may become overly acidic if not managed.Lifestyle and diet, particularly with respect to foals and adult horsesin training, may exacerbate this acidity, predisposing the horse toulcers.

Ulcers may result from imbalances in hydrochloric acid, pepsin, bileacids, and organic acids present in gastric fluids and protectiveelements, such as bicarbonate and mucus. Due to the structuraldifferences in various sections of the equine stomach, the mode ofaction in ulcer development is varied due to various concentrations ofunderlying gastric fluid components. The severity of ulceration in thestomach is due to the degree and length of time of exposure. Factorsthought to influence the onset of an ulcer-causing fluid imbalance arefasting (feed deprivation), stress, reduced gastric motility, diet, anddesquamation. Feed deprivation or irregular feeding has been shown toreduce stomach pH, which could play a direct role in the development ofequine stomach ulcers. In addition to irregular feeding, stress inducedimbalances are particular present in horses in training. Exercise andstress create prolonged exposure to gastric fluids, and a reduction ingastric motility. Delayed gastric emptying (motility) has beenassociated with ulcer formation. Furthermore, equine diet, particularlythat of a horse in training, has been linked to the presence of gastriculcers.

Horses in training are often fed diets high in fermentablecarbohydrates. These carbohydrates, when fermented, create a byproductof volatile fatty acids (VFA). VFAs penetrate the mucosal lining of thestomach and are linked to cell damage, inflammation, and ulceration.Horses have been found to have significant levels of VFAs present whenin training. Diagnosing gastric ulcers of the equine stomach istypically confirmed through endoscopic examination. There are, however,clinical signs that present depending on whether the horse is a foal oradult. The foal may present with colic, poor appetite, diarrhea, excesssalivation (ptyalism), grinding of teeth (bruxism), intermittentnursing, or dorsal recumbency. Adult horses with ulcers often presentwith lack of appetite, changes in demeanor, decreased performance,reluctance to train, reduced body condition, rough hair coat, weightloss, excessive recumbency, and low-grade colic.

Current treatments include changes to diet, lifestyle, or pharmaceuticalmanagement. Pharmaceutical management may be administered throughOmeprazole paste (GastroGard, Merial Limited). Omeprazole is an acidpump inhibitor that inhibits the production of stomach acid. Omeprazolepaste is the only FDA cleared pharmaceutical for the treatment of equinegastric ulcers. Full doses are administered for the treatment ofexisting gastric ulcers, while half doses are typically used for theprevention of gastric ulcers. Long-term use of Omeprazole is not,however, without controversy; as long-term exposure is thought toincrease the risk of fracture, particularly in horses in training.Accordingly, improved compositions and methods for treating equineulcers are urgently required.

SUMMARY OF THE INVENTION

The invention provides compositions comprising chitosan, manuka honeyand one or more additional components that promotes digestive health(e.g., inulin, probiotics) for the treatment and prevention of gastriculcers (e.g., esophageal, stomach, or duodenum) in a mammal (e.g.,equine).

In one aspect, the invention features a composition for the treatment orprevention of an ulcer containing any of the ingredients in Table 1 ormanuka honey and a biopolymer that is any one or more of chitosan,cellulose, collagen, and alginate in a form suitable for oraladministration. In one embodiment, the composition further containsslippery elm. In another embodiment, the composition further containsinulin or another probiotic. In another embodiment, the compositionfurther contains aloe water and/or aloe vera. In another embodiment, thecomposition further contains one or more acids selected from the groupconsisting of ascorbic acid, citric acid, malic acid, apple cidervinegar, rice vinegar or other acetic acids or vinegars. In anotherembodiment, the composition further contains lecithin. In anotherembodiment, the composition further contains a flavoring selected fromthe group consisting of apple, apple butter, apple pectin, peppermint,and citrus. In another embodiment, the composition further contains aplant-based composition selected from the group consisting of a pomace,powder, liquid, concentrate, and a lyophilized component. In anotherembodiment, the composition further contains a fungal composition (e.g.,derived from a mushroom, such as schizophyllan) or a plant-basedcomposition derived from a fruit (e.g., banana, berry, apple, or citrusfruit, such as orange, lemon, lime), vegetable (e.g., beet, beetroot,other root-based flora), grain or herb. In one embodiment, theplant-based composition has anti-inflammatory activity. In anotherembodiment, the composition further containing a preservative that isascorbic acid, potassium sorbate or citric acid. In another embodiment,the composition further containing a polyol selected from the groupconsisting of glycerol, glycerine, glycerin, maltitol, sorbitol,xylitol, erythritol, or isomalt. In another embodiment, the chitosan ispresent in the range of 0.00001 to 10 wt %, from 0.00001 to 5 wt %, orfrom 0.00001 to 3 wt %. In another embodiment, the manuka honey ispresent in the range of 0.00001 to 10 wt %, from 0.00001 to 5 wt %, orfrom 0.00001 to 3 wt %. In another embodiment, the lecithin is presentin the range of 0.00001 to 25 wt %, preferably from 0.00001 to 10 wt %.In another embodiment, acids are present individually in the range of0.00001 to 10 wt %, from 0.00001 to 5 wt %, from 0.00001 to 3 wt %, andcollectively not more than 5% of the composition. In another embodiment,the composition is a liquid, gel, semi-liquid, semi-solid, paste, orsolid form. In another embodiment, water makes up the balance of thesolution, and represents no less than 60 wt % of the entire solution. Inanother embodiment, the composition is formulated for delivery through asyringe, formed into a powder, feed, feed additive, or treat. In anotherembodiment, the composition further contains a soluble or insolublenano-particulate. In another embodiment, the nano-particulate is Silver,Magnesium, Copper, Arsenic, Zinc, Tellurium, or Mercury. In anotherembodiment, the composition contains a soluble or insolubleantimicrobial, antifungal, or antibacterial agents.

In another aspect, the invention features a pharmaceutical compositioncontaining the composition of a previous aspect.

In another aspect, the invention features a method for treatingdigestive distress in a mammal, the method involving administering tothe mammal an effective amount of a composition of any previous aspect.

In another aspect, the invention features a method for treating orpreventing a gastric ulcer, the method involving administering to theanimal an effective amount of a composition of any previous aspect. Inone embodiment, the mammal has Equine Gastric Ulcer Syndrome (EGUS).

In another aspect, the invention features a method for maintaining ahealthy digestive environment, the method involving administering to theanimal an effective amount of a composition of any previous aspect.

In various embodiments of the above aspects, the mammal is an equine,bovine, ovine, feline, or canine.

Definitions

By “alginate” is meant the sodium salt of alginic acid. In particularembodiments, alginic acid refers to a linear copolymer withhomopolymeric blocks of (1-4)-linked 1-D-mannuronate (M) and its C-5epimer .alpha.-L-guluronate (G) residues, respectively, covalentlylinked together in different sequences or blocks.

By “chitosan” is meant a chitin-derived polymer that is at least 20%deacetylated. Preferably, chitosan is at least about 50% deacetylated.Chitin is a linear polysaccharide consisting of (1-4)-linked2-acetamido-2-deoxy-b-D-glucopyranose. Chitosan is a linearpolysaccharide consisting of (1-4)-linked2-amino-2-deoxy-b-D-glucopyranose.

By “acid treated chitosan” is meant chitosan that is solubilized in anacidic solution.

By “collagen” is meant a protein component of an extracellular matrixhaving a tertiary structure that includes polypeptide chainsintertwining to form a collagen triple helix or having a characteristicamino acid composition comprising Gly-X-Y repeat units, or a fragmentthereof. Collagens useful in the methods of the invention include anycollagen known in the art (e.g., one of collagen type 1-29). By“composite” is meant a mixture of materials.

By “agent” is meant any small compound, macromolecule, biopolymer,polypeptide, or fragments thereof.

By “ameliorate” is meant decrease, suppress, attenuate, diminish,arrest, or stabilize the development or progression of a disease.

By “alteration” is meant a change (increase or decrease) in theexpression levels or activity of a gene or polypeptide as detected bystandard art known methods such as those described herein. As usedherein, an alteration includes a 10% change in expression levels,preferably a 25% change, more preferably a 40% change, and mostpreferably a 50% or greater change in expression levels.

By “antimicrobial” is meant an agent that inhibits or stabilizes theproliferation or survival of a microbe. In one embodiment, abacteriostatic agent is an antimicrobial. In other embodiments, anyagent that kills a microbe (e.g., bacterium, fungus, virus) is anantimicrobial.

By “anti-inflammatory” is meant an agent that reduces the severity orsymptoms of an inflammatory reaction in a tissue.

By “clinician” is meant any healthcare provider. Exemplary cliniciansinclude, but are not limited to, doctors, veterinarians, osteopaths,physician's assistants, emergency medical technicians, medics, nursepractitioners, and nurses.

In this disclosure, “comprises,” “comprising,” “containing” and “having”and the like can have the meaning ascribed to them in U.S. Patent lawand can mean“includes,” “including,” and the like; “consistingessentially of” or “consists essentially” likewise has the meaningascribed in U.S. Patent law and the term is open-ended, allowing for thepresence of more than that which is recited so long as basic or novelcharacteristics of that which is recited is not changed by the presenceof more than that which is recited, but excludes prior art embodiments.

“Detect” refers to identifying the presence, absence or amount of theanalyte to be detected.

By “disease” is meant any condition or disorder that damages orinterferes with the normal function of a cell, tissue, or organ. In oneexample, a disease is an ulcer or other wound affecting thegastrointestinal system of a mammal.

By “effective amount” is meant the amount of an agent required toameliorate the symptoms of a disease relative to an untreated patient.The effective amount of active agent(s) used to practice the presentinvention for therapeutic treatment of a disease varies depending uponthe manner of administration, the age, body weight, and general healthof the subject. Ultimately, the attending physician or veterinarian willdecide the appropriate amount and dosage regimen. Such amount isreferred to as an “effective” amount.

By “polymer” is meant a natural or synthetic organic molecule formed bycombining smaller molecules in a regular pattern.

The terms “isolated,” “purified,” or “biologically pure” refer tomaterial that is free to varying degrees from components which normallyaccompany it as found in its native state. “Isolate” denotes a degree ofseparation from original source or surroundings. “Purify” denotes adegree of separation that is higher than isolation. A “purified” or“biologically pure” protein is sufficiently free of other materials suchthat any impurities do not materially affect the biological propertiesof the protein or cause other adverse consequences.

Ranges provided herein are understood to be shorthand for all of thevalues within the range. For example, a range of 1 to 50 is understoodto include any number, combination of numbers, or sub-range from thegroup consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

By “subject” is meant a mammal, including, but not limited to, a humanor non-human mammal, such as a bovine, equine, canine, ovine, or feline.

As used herein, the terms “treat,” treating,” “treatment,” and the likerefer to reducing or ameliorating a disorder and/or symptoms associatedtherewith. It will be appreciated that, although not precluded, treatinga disorder or condition does not require that the disorder, condition orsymptoms associated therewith be completely eliminated.

As used herein, the terms “prevent,” “preventing,” “prevention,”“prophylactic treatment” and the like refer to reducing the probabilityof developing a disorder or condition in a subject, who does not have,but is at risk of or susceptible to developing a disorder or condition.

By “reference” is meant a standard or control condition.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compositions comprising chitosan, manuka honeyand one or more additional components that promotes digestive health(e.g., inulin, probiotics) for the treatment and prevention of gastriculcers (esophageal, stomach, or duodenum) in a mammal (e.g., equine).

The present invention approaches ulcer treatment from a wound careperspective, whether protecting and preventing ulcers or treatingexisting ulcers.

A nutraceutical composition of the invention may be used temporarily(e.g., for a few days, weeks) or may be used on an on-going basis (e.g.,months, years) as a permanent daily use supplement, or may be used totreat an acute condition following the onset or suspicion that ulcersymptoms are present.

Equine Digestive Health

Ulceratic lesions in the mucosal lining of the digestive tract arecommon in equines (e.g., horses) used for recreation, commercial and/oragricultural purposes. In particular, many competitive activities,including racing, dressage, showjumping, endurance events and westernperformance, lead to ulcers and related symptoms in horses participatingin these activities. Depending on the intensity of training, theprevalence of gastric ulcers in horses can affect from 10% to 90% ofparticipating horses. Apart from exercise, many factors contribute tothe development of ulcers, for example, transport to and from showgrounds, stall confinement in unfamiliar surroundings, grain-baseddiets, ingestion of anti-inflammatory agents, and/or irregular feedingschedules.

The symptoms of ulcers in affected animals can be subtle and may includeirritability and changes in attitude and behavior, poor appetite, anddecreased performance and energy. These symptoms may also be exhibitedwith other symptoms, such as lethargy; musculo/skeletal discomfort andpain; decline or deterioration in body condition and/or appearance (dullhair coat); weight loss; alterations in eating or drinking patterns;resistance to grooming; reluctance or refusal to performing certaintasks; and behavior indicating discomfort, such as pawing or laying downexcessively. Still other signs that may correlate with ulcers in theanimal include sensitivity in the flank area and girthiness; cribbing(windsucking); wood-chewing; and weaving in the stall, an (atypical)unwillingness to work or cooperate, and resistance under saddle. Foalsafflicted with an ulcer may also grind their teeth or lay on theirbacks. Once an ulcer is suspected or determined in a non-human animal,such as horses, ponies, camels, donkeys, or mules, particularly, horses,the methods of the invention are useful in treating gastric and coloniculcers and/or the symptoms of such ulcers in the animal.

The invention provides methods directed to treating gastric and/orcolonic ulcers and the uncomfortable and often painful discomfort thatthey cause in both young and adult horses and other non-human animals.The methods are effective in reducing and/or alleviating the ulcers andthe symptoms that afflict such animals in need thereof. In particular,the methods are directed to the treatment of ulcers in horses,particularly ulcers of the colon that can lead to blood loss,irritability and poor absorption of nutrients in ulcerated young andadult animals. Treatment and prevention of ulceratic conditions inhorses with the methods and compositions of the invention can positivelyimpact and improve the performance of horses that are expected toperform at peak proficiency, including leisure and recreational horsesand show horses, especially training and race horses.

Animals (horses) having a history of gastric and/or colonic ulcers maybenefit from proactive treatment with the compositions of the inventionto decrease or abrogate the chances of developing ulcers or therecurrence of ulceration. During and following a course of treatmentwith the compositions and methods described herein, an animal beingtreated can be monitored for a change in its clinical behavior todetermine that the gastric and colonic ulceratic conditions areimproved, reduced, or eliminated. Preferably, the animal is examined viaendoscopy or gastroscopy to confirm improvement and/or healing ofulceratic lesions, and prior to discontinuing therapy with the methodsand compositions of the invention. Endoscopic examination involvesshort-term tranquilization of the animal to reduce stress to the animalfrom the procedure. Thereafter, an endoscope is inserted through theanimal's nostril and guided down the esophagus into the stomach whereinthe light and camera on the endoscope's terminus allow observation ofthe stomach lining. A complete endoscopic evaluation can take about 10to 20 minutes and is safe for the animal.

Nonlimiting examples of animals affected by gastrointestinal ulcers andtreatable by the methods and formulations of the invention particularlyinclude young (foals) and adult equine animals (horses). Other animalsthat may suffer from ulcers and benefit from treatment and prevention bythe methods and compositions described herein include canines, felines,young camels (calves) and adult camels. In addition, young cattle(calves), pigs (piglets), sheep (lambs), goats (kids), horses (foals)and adult animals, including, cattle, steer, bison, buffalo, goats,sheep and rams, may be treated according to the methods of theinvention. In some embodiments, a composition of the invention is usedto treat a human.

Chitosan

Chitosan is a naturally occurring linear polysaccharide composed ofrandomly distributed β-(1-4)-2-amino-2-D-glucosamine (deacetylated) andβ-(1-4)-2-acetamido-2-D-glucoseamine (acetylated) units. Chitosan isderived from chitin, a naturally occurring polymer. Chitin is a white,hard, inelastic, nitrogenous polysaccharide isolated from fungi,mollusks, or from the exoskeletons of arthropods (e.g., crustaceans,insects). The major procedure for obtaining chitosan is the alkalinedeacetylation of chitin with strong alkaline solution. Generally, theraw material is crushed, washed with water or detergent, and ground intosmall pieces. After grinding, the raw material is treated with alkaliand acid to isolate the polymer from the raw crushed material. Thepolymer is then deacetylated by treatment with alkali. Chitin andchitosan differ in their degrees of deacetylation (DDA). Chitin has adegree of deacetylation of 0% while pure chitosan has a degree ofdeacetylation of 100%. Typically, when the degree of deacetylation isgreater than about 50% the polymer is referred to as chitosan.

Chitosan is a cationic weak base that is substantially insoluble inwater and organic solvents. Typically, chitosan is fairly soluble indilute acid solutions, such as acetic, citric, oxalic, proprionic,ascorbic, hydrochloric, formic, and lactic acids, as well as otherorganic and inorganic acids. Chitosan's charge gives it bioadhesiveproperties that allow it to bind to negatively charged surfaces, such asbiological tissues present in a gastrointestinal tract of an animal.

In the body chitosan is degraded by lysozyme, N-acetyl-o-glucosaminidaseand lipases. Lysozyme degrades chitosan by cleaving the glycosidic bondsbetween the repeating chitosan units. The byproducts of chitosandegradation are saccharides and glucosamines that are gradually absorbedby the body.

This biopolymer material has been used medically, and is valued for itsbiocompatibility, degradation and absorption properties, hemostaticproperties, and for promoting the healing process in damaged tissues.Chitosan has also been linked in scientific literature as beingantimicrobial, bacteriostatic, anti-inflammatory, and for reducingitching. Chitosan has been used as coating, a composition binder, and asan active ingredient in pharmaceutical or, ceutical applications.

Collagen

Collagen is the most abundant structural protein in the body, existingas the foremost component of the extracellular matrix (ECM). Most typesof collagen contain a unique tertiary structure that includes threeindividual right-handed helical polypeptide chains intertwining to forma left-handed helix. Collagen has a characteristic amino acidcomposition comprised of Gly-X-Y repeat units. Collagen is used in avariety of medical applications including hemostatic materials,biocompatible coatings, drug delivery and tissue engineering.Collagen-based biomaterials are also used in soft-tissue engineering andrepair. In the past two decades, a multitude of medical productscomposed of collagen have been approved by the FDA, and many areavailable as commercial products, including collagen-based cornealshields, anti-infectious catheters, tissue sealants, hemostatic sponges,and topical wound dressing products. Collagen is also used as a tissueengineering substrate for skin, bone, and blood vessel replacement.

Healing Agents

The invention provides pharmaceutical and/or nutraceutical compositionscomprising a biopolymer (e.g., chitin, chitosan, collagen, cellulose,alginate, dextrose) and one or more natural healing agents, includingbut not limited to manuka honey, and optionally comprising one or moreof herbal supplements, probiotics, acids, fruits, vegetables, plants(flora), preservatives, polyols, medicaments, antimicrobial additives,antibacterial additives, antifungal additives, or nano-particles. Thecurrent embodiment may be provided as a liquid or solid, in the form ofpowder, hydrogel, paste, pellets, or larger solid compositions.

The invention provides a chitosan solution with varying viscositycomprising natural healing agents, such as manuka honey. Manuka honey isa highly viscous type of honey that has medical applications, as well asantimicrobial properties.

In particular embodiments, a chitosan composition described hereincomprises an herbal supplements, including but not limited to slipperyelm (Ulmus fulva). Slippery elm is useful in the treatment of gastriculcers. Slippery elm is an herbal supplement derived from the inner barkof the Slippery Elm tree. This herbal supplement is high in mucilage,which becomes a thick gel when in solution and can be used to lubricateand protect wounds, boils, ulcers, and other sores on the body. Further,slippery elm can be used to coat the lining of the stomach to protectand soothe irritations present in the stomach. The inner bark of theSlippery Elm tree is typically dried, through lyophilization or anothermethod, and ground into a powder (dried elm powder), which can be addedto a composition of the invention.

In particular embodiments, a chitosan composition described hereincomprises a probiotic. Probiotics useful in a composition of theinvention, including but not limited to inulin may be added to acomposition of the invention to support digestive health. Inulin is aprobiotic fiber that not only supports digestive health, but that alsoinhibits ulcer formation by supporting vitamin absorption, inhibitingcertain undesirable bacterial species in the gut, and supporting healthymotility.

In particular embodiments, a chitosan composition described hereincomprises one or more acids including, but not limited to, acetic orcitric acid, which may be used as a solvent, preservative, flavoring,etc. Acids may be used, for example, as a solvent to dissolve abiopolymer of the invention. In one embodiment a polymer that is presentin powder form is dissolved in a liquid solution with varying viscosity.This may be performed by pouring a known mass of biopolymer componenttogether with an acid solvent solution; and mixing until the powderbiopolymer is fully dissolved into a liquid solution. Other agents maybe added to solution. Depending on viscosity, it may be necessary toapply negative pressure (a vacuum) to the resulting solution prior tofilling the container of choice (bottle, tube, syringe, etc.). Further,acids may be used as a preservative to prevent spoilage of the resultingsolution, and to maintain or increase shelf life. Acids, such as citricor malic acid, may also be used to affect the flavor profile of theresulting solution as well.

In particular embodiments, a chitosan composition described hereincomprises lecithin. Lecithin is the common name for a fat calledphosphatidylchoilne. Lecithin upon entering the stomach, breaks downinto a mixture of phospholipids that bind to the lining of stomach,thereby providing a protective barrier. Further, lecithin is known tostrengthen the mucosa of the stomach lining by interacting with thelining at a cellular level. Additionally, lecithin has been shown toreduce stress and anxiety in horses in training, a known cause ofincreased prevalence of ulcers.

In particular embodiments, a chitosan composition described hereincomprises one or more natural and/or synthetic flavorings to create apalatable nutraceutical. Animals, in particular, are unlikely to showwillingness to consume a nutraceutical unless it is flavored in a mannerthat is appealing. Common flavorings favored by equines include, but arenot limited to apple, peppermint, or citrus flavors.

In particular embodiments, a chitosan composition described hereincomprises one or more fruits, vegetables, herbs, or other plant-basedcompositions. Advantageously, such fruits, vegetables, and herbs haveantioxidant or anti-inflammatory properties. In one particularembodiment, a chitosan composition comprises a plant-based pomace.Pomace is the pulpy residue that remains after the plant materials havebeen pressed or crushed to extract its juice. Fruits, vegetables, herbs,and plants may be provided in the form of pomace, such as a powder,liquid, solid or concentrated form based on the whole or a part of theflora. Common examples of pomace include, but are not limited to, applepowder, beet powder, beetroot powder, banana or banana peel powder, andcompositions from berries (for example, blueberry, blackberry,raspberry, strawberry, cranberry).

In particular embodiments, a chitosan composition described hereincomprises a polyol, including but not limited to glycerol, glycerine, orglycerin, maltitol, sorbitol, xylitol, erithritol, or isomalt, which area group of sugar alchohols that may be used to provide sweetening whilemaintaining moisture content in the resulting solution. In oneembodiment, one or more polyols are added to a composition of theinvention to maintain the moisture of the composition, binding thenutraceutical composition in paste form for optimum ingredient activity,while additionally affecting the flavor profile.

The resulting solution, which may vary in viscosity, may in anotherembodiment have a nano-particulate dispersed within the solution.Nano-particulate silver and nano-particulate magnesium may be used toprevent bacterial, microbial, or fungal contamination of the solutionitself or in the treated local environment. Further nano-particulatemetals and non-metals have been shown to interact at the cellular level,which may have a preservative, or active pharmaceutical or medicinaleffect. Bioactive ingredients, such as bioactive metals (e.g., Copper,Arsenic, Zinc, Tellurium, Mercury) in varying size ranges may also beadded.

In one embodiment, the invention provides a composition comprisingchitosan and manuka honey in any proportion (e.g., 0.5:10, 1:10, 2:20,3:10, 4:10, 5:10, 6:10, 7:10, 8:10, 9:10, 10:0.5, 10:1, 10:2, 10:3,10:4, 10:5, 10:6, 10:7, 10:8, 10:9, 1:1), further characterized by theaddition of one or more of the following:

-   -   Slippery elm (dried elm powder),    -   Inulin as a probiotic,    -   Ascorbic, citric, and malic acids,    -   Lecithin,    -   Apple Pectin,    -   Apple (powder)    -   Beetroot (powder)    -   Potassium Sorbate (as a preservative)    -   Aloe Vera    -   Glycerin

Pharmaceutical and Nutraceutical Formulations

In one embodiment, a composition of the invention for use in treating orpreventing ulcers is a paste or a gel composition. Admixed and/orotherwise associated or combined with the gel or paste phase is one ormore healing agents formulated for oral administration. By way ofexample, a composition of the invention is formulated for oral or buccaladministration, including, without limitation, roof of mouth, dental,periodontal, or esophageal administration. In particular embodiments,food source (animal feed), nutrition source, libation source, or foodand/or drink supplement could be used. In an embodiment, the combinationproduct could be provided in an aqueous formulation, administered to theanimal as a drench or directly from a ready-to-use (RTU) bottle directedto the esophageal cavity. In a related embodiment, administration canalso be by inclusion in the regular or special diet of the animal, suchas in a functional food for the animals in need, or as a dietarysupplement or food supplement for administration to an animal in needthereof according to the present invention.

Nonlimiting examples of suitable carriers, excipients, diluents andvehicles include lactose, dextrose, sucrose, sorbitol, mannitol,starches, gum acacia, calcium phosphate, alginates, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, collagen,gelatin, syrup, methyl cellulose, methyl- and propylhydroxybenzoates,talc, magnesium, stearate, water, mineral oil, edible oils, and thelike. In particular embodiments, the carrier is a juice or water (e.g.,coconut water, aloe water). The formulations can also includelubricating agents, wetting agents, emulsifying and suspending agents,preserving agents, sweetening agents or flavoring agents.

Formulations of the invention include ranges of the followingingredients in

TABLE 1 Ingredient Percentage Water 25-40  Aloe Water 25-40  AppleButter 15-40  Apple Pectin 1-15 Lecithin 1-15 Xylitol 1-15 Inulin 1-15Glycerin 1-15 Manuka honey 1-10 Malic acid 1-10 Chitosan 1-10 Ascorbicacid 0.1-1.0  Slippery Elm 0.1-1.0  Citric acid 0.1-1.0  Potassiumsorbate 0.01 Apple powder/flavoring 10-30  Sorbitol 1-10 Beet rootpowder 1-10 Hyaluronic acid 1-25 schizophyllan 1-10

The compositions of the invention are administered, for example, on adaily basis. The amount administered can range from about 1 to about 10mg/kg/day once, twice or more daily; or from about 1 to about 5mg/kg/day, from about 1 to about 8 mg/kg/day, from about 1 to about 10mg/kg/day, or from about 2 to about 4 mg/kg/day once, twice or moredaily. In other embodiments, a composition of the invention isadministered, for example, twice daily, three times daily, four timesdaily, or more than four times daily. The amount of the compositionadministered will vary with the weight of the animals. A foal, whichweighs about 50 kg would receive about 1, 3, 5 or 10 g of a compositionof the invention per day, i.e., about 1 g/50 kg, 3 g/50 kg, 1 g/10 kg,or 1 g/5 kg per day. In contrast, a full grown horse weighing 500 kg,might receive up to 80 kg per day (i.e., 1 g/25 kg, 2 g/25 kg, 3 g/25kg, 4 g/25 kg, 1 g/5 kg, 10 g/25 kg, 20 g/25 kg.)

Doses administered once or multiple times per day can be given forconsecutive days, e.g., two days, three days, four days, five days, six,days, seven days, or more, in some embodiments. A dose administeredmultiple times per day may embrace two, three, four, five, six, ten, ormore times per day. Other dosing schedules, such as every other day, orevery third day, every fourth day, etc. are embraced by the invention.In addition, one having skill in the art will appreciate that doses andamounts administered to the animal can vary, given the wide range ofweights of the animals undergoing treatment, as well as the animalspecies and type of digestive system, e.g., ruminant or non-ruminant.

Methods of Use

The invention is directed to methods of treating and preventing ulcersof the gastrointestinal region in young and adult animals, particularlyequine animals, such as horses that can be naturally high-strung and canbecome stressed as a result of events in their habitats and lifestyles,as well as from endurance activities and performances expected of them.The method of the invention comprises administering to an animal in needof ulcer treatment or prevention. Treating the ulcers can also involvedecreasing the discomfort and pain associated with ulceratic lesions inthe animal undergoing treatment.

The non-human young and adult animals for which the treatment methodsare suitable may include different animal types, genera, or species. Ingeneral, young and adult farm animals, animals bred or kept for variouspurposes, such as sport (e.g., racing, riding, dressage), transport,domestic, companion (e.g., dogs, cats), industrial uses (e.g. hauling,pulling, plowing), and the like, are particularly amenable to treatmentaccording to the methods of the invention. For example, encompassed bythe methods of the invention is the treatment of adult or youngnon-human animals, such as camels (calves), sheep (lambs), rams, horses(foals), pigs (piglets), goats (kids), bison/buffalo (calves), llamas,donkeys, mules, yaks, etc. Neonatal, young and adult exotic animals,such as zoo animals of various species, are also embraced by thetreatments of the invention. In preferred aspects, young and adulthorses are animal subjects that are particularly amenable to the methodsand compositions of the invention.

Example 1: Formula 1

A paste for oral delivery to an equine was produced. The paste containedthe following materials:

Apple powder/flavoring . . . 17.22%Water/aloe water . . . 53.2% (50/50 split)

Lecithin . . . 6.24%

Apple pectin . . . 4.48%

Sorbitol . . . 4.15% Glycerin . . . 2.97%

Manuka honey . . . 2.2%Beet root powder . . . 2.2%

Inulin . . . 2.02%

Malic acid . . . 2.02%

Chitosan . . . 1.65% Slippery elm . . . 0.81%

Ascorbic acid . . . 0.37%Citric acid . . . 0.26%Potassium sorbate . . . 0.15%

Under a veterinarian's supervision, the formulation was administered torace horses in training suffering from ulcers. An improvement in thehorse's physical performance was observed, indicating that theadministration had been effective in ameliorating symptoms associatedwith the presence of ulcers. In at least one horse, an improvement inhind gut ulcers was observed using the Succeed Equine Fecal Blood Test™,which measures albumin and hemoglobin as indicators of gastrointestinalinjury.

Example 2: Formulation 2

A composition for delivery to an equine was produced. The compositioncontained the following materials:

Water/Aloe Water (50/50 ratio)—37.6%

Apple Butter—29.1% Apple Pectin—7.49% Lecithin—7.07% Xylitol—4.58%Inulin—3.33% Glycerin—3.33%

Manuka honey—2.5%Malic acid—2.12%

Chitosan—1.87%

Ascorbic acid—0.42%

Slippery Elm—0.42%

Citric acid—0.25%Potassium sorbate—0.08%Under a veterinarian's supervision, the formulation was administered tohorses suffering from ulcers.

OTHER EMBODIMENTS

From the foregoing description, it will be apparent that variations andmodifications may be made to the invention described herein to adopt itto various usages and conditions. Such embodiments are also within thescope of the following claims.

The recitation of a listing of elements in any definition of a variableherein includes definitions of that variable as any single element orcombination (or subcombination) of listed elements. The recitation of anembodiment herein includes that embodiment as any single embodiment orin combination with any other embodiments or portions thereof.

All patents and publications mentioned in this specification are hereinincorporated by reference to the same extent as if each independentpatent and publication was specifically and individually indicated to beincorporated by reference.

What is claimed is:
 1. A composition for the treatment of a gastriculcer, the composition comprising dried elm powder and a biopolymerselected from the group consisting of chitosan, cellulose, collagen, andalginate in a form suitable for oral administration.
 2. The compositionof claim 1, further comprising any one or more of the following: manukahoney, inulin or another prebiotic; ascorbic acid, citric acid, malicacid, acetic acid, apple cider vinegar, rice vinegar or other vinegar;lecithin; a flavoring selected from the group consisting of apple, applebutter, apple pectin, peppermint, and citrus; and a polyol selected fromthe group consisting of glycerol, glycerine, glycerin, maltitol,sorbitol, xylitol, erythritol, or isomalt.
 3. The composition of claim1, wherein the dried elm powder comprises a slippery elm herbalsupplement.
 4. The composition of claim 1, further comprising a carrierselected from the group consisting of water, coconut water, aloe water,aloe vera, and juice.
 5. The composition of claim 1, further comprisinga plant-based composition that is derived from a fruit or vegetable andthat has a form selected from the group consisting of a pomace, powder,liquid, concentrate, and lyophilized component.
 6. The composition ofclaim 5, wherein the fruit is a banana, berry, apple, or citrus fruitand wherein the vegetable is beet, beetroot, or other vegetable root. 7.The composition of claim 1, further comprising a preservative that isascorbic acid, potassium sorbate or citric acid.
 8. The composition ofclaim 1, wherein the chitosan is present in the range of 0.00001 to 10wt %, from 0.00001 to 5 wt %, or from 0.00001 to 3 wt %; and wherein thedried elm powder is present in the range of from 0.1 to 1 wt %.
 9. Thecomposition of claim 1, wherein acids are present individually in therange of 0.00001 to 10 wt %, from 0.00001 to 5 wt %, from 0.00001 to 3wt %, and collectively not more than 5% of the composition.
 10. Thecomposition of claim 1, wherein the composition is a liquid, gel,semi-liquid, semi-solid, paste, or solid form.
 11. The composition ofclaim 1, further comprising water or a carrier that is not water,wherein the water or carrier makes up the balance of the composition,and represents no less than 60 wt % of the entire composition.
 12. Thecomposition of claim 1, wherein the composition is formulated fordelivery through a syringe, or formed into a powder, feed, feedadditive, or treat.
 13. The composition of claim 1, further comprising asoluble or insoluble nano-particulate.
 14. The composition of claim 13,wherein the nano-particulate is silver or magnesium.
 15. The compositionof claim 1, further comprising a soluble or insoluble antimicrobial,antifungal, or antibacterial agent.
 16. A pharmaceutical compositioncomprising the composition of claim
 1. 17. A method for treatingdigestive distress in a mammal, the method comprising administering tothe mammal an effective amount of the composition of claim
 1. 18. Amethod for treating a gastric ulcer in an animal, the method comprisingadministering to the animal an effective amount of the composition ofclaim 1, optionally wherein the animal has Equine Gastric Ulcer Syndrome(EGUS).
 19. The method of claim 18, wherein the animal is an equine,bovine, ovine, feline, or canine animal.
 20. A method for maintaining ahealthy digestive environment in an animal, the method comprisingadministering to the animal an effective amount of a composition ofclaim 1.